Apoptosis can potently defend against intracellular pathogens by directly killing microbes and eliminating their replicative niche. However, the reported ability of Mycobacterium tuberculosis to restrict apoptotic pathways in macrophages in vitro has led to apoptosis being dismissed as a host-protective process in tuberculosis despite a lack of in vivo evidence. Here we define crucial in vivo functions of the death receptor-mediated and BCL-2-regulated apoptosis pathways in mediating protection against tuberculosis by eliminating distinct populations of infected macrophages and neutrophils and priming T cell responses. We further show that apoptotic pathways can be targeted therapeutically with clinical-stage compounds that antagonize inhibitor of apoptosis (IAP) proteins to promote clearance of M. tuberculosis in mice. These findings reveal that any inhibition of apoptosis by M. tuberculosis is incomplete in vivo, advancing our understanding of host-protective responses to tuberculosis (TB) and revealing host pathways that may be targetable for treatment of disease.

细胞凋亡可以通过直接杀死微生物并消除其复制生态位来有效抵御细胞内病原体。然而，尽管缺乏体内证据，据报道结核分枝杆菌在体外限制巨噬细胞凋亡途径的能力导致细胞凋亡被认为是结核病的宿主保护过程。这里我们定义了关键的体内死亡受体介导的和 BCL-2 调节的细胞凋亡通路在通过消除不同的受感染巨噬细胞和中性粒细胞群并引发 T 细胞反应来介导对结核病的保护中的功能。我们进一步表明，细胞凋亡途径可以通过临床阶段的化合物进行治疗，这些化合物拮抗细胞凋亡抑制剂 (IAP) 蛋白以促进小鼠结核分枝杆菌的清除。这些发现表明，结核分枝杆菌对细胞凋亡的任何抑制在体内都是不完全的，这促进了我们对宿主对结核病 (TB) 保护反应的理解，并揭示了可作为治疗疾病的目标的宿主途径。